This project is designed to directly identify the hypophysiotropic elements of the ACTH regulatory system in the rat. Hypophysiotropic portal blood levels of corticotropin-releasing factor, angiotensin II and arginine vasopressin will be measured during paradigms demonstrated to reliably evoke ACTH secretion, transient 15% hemmorhage and insulin-induced hypoglycemia. The relative importance of these putative releasing agents and of adrenomedullary catecholamines to the overall ACTH secretor response will be assessed using antagonists or antibodies to these agents. Modulation of hypothalamic release of putative releasing agents and of pituitary sensitivity to them will be measured under conditions of basal or chronically elevated corticosterone. Finally, chronic studies will be undertaken in the awake rat using peripheral blood sampling and continuous local perfusion of the median eminence in an effort to correlate adenohypophysial ACTH secretion with hypothalamic secretion of putative releasing factors. Besides hemmorhage and hypoglycemia, changes in secretion during the circadian rhythm, ether stress and restraint stress will be examined in chronic preparations. Data obtained will be used to construct a mathematical model of hypophysiotropic regulation of ACTH secretion.